Multi‐Omics Identifies CTSS as a Susceptibility Gene and Actionable Target That Regulates Melanocyte MHC ‐ II Expression and Survival in Vitiligo

Vitiligo is a common autoimmune disorder characterized by melanocyte loss, yet the molecular mechanisms linking genetic susceptibility to melanocyte dysfunction remain incompletely understood. In this study, we integrated multi-tissue transcriptome-wide association studies (TWAS), summary-data-based Mendelian randomization (SMR), and colocalization analyses to identify causal genes within vitiligo susceptibility loci. CTSS was prioritized as a candidate susceptibility gene at the 1q21 locus. Single-cell and bulk RNA sequencing analyses revealed that CTSS was significantly upregulated in lesional melanocytes and associated with an MHC class II-related transcriptional program. Mechanistically, CTSS expression was induced downstream of IFN-γ/STAT1 signaling and positively associated with oxidative phosphorylation, suggesting potential metabolic regulation. Functional experiments demonstrated that CTSS overexpression was associated with increased HLA-DRA expression, enhanced apoptosis, and reduced proliferation in melanocytes. Furthermore, the selective CTSS inhibitor RO5459072 attenuated HLA-DRA induction in vitro. Clinically, serum CTSS levels were elevated in patients with active vitiligo, showed moderate diagnostic performance for disease activity (AUC = 0.787), and correlated with disease severity. Collectively, these findings suggest that CTSS may serve as a key mediator linking genetic susceptibility, inflammatory signaling, and metabolic status in vitiligo. Rather than establishing melanocytes as professional antigen-presenting cells, our results indicate that melanocytes may acquire partial immunogenic features under inflammatory stress conditions. This study provides new insights into melanocyte-intrinsic mechanisms underlying vitiligo pathogenesis and highlights CTSS as a potential therapeutic target for future investigation.